Derivatives of dihydro-pyridone -and



pentyl, 1 cyclohexyl Patented Nov. 16, 1943 DERIVATIVES F DIHYnRo PYnInonEANn j PROCESS FOR THEIR. MANUFACTURE",

Max Hoifer, Basel, Switzerland, assignor" to Hofimann-La Roche Inc., Nutley, N. J.', a corporation of New Jersey No Drawing, Application February 18, 1941, Se 'iigal No. 379,547.. A In Switzerland March 29, 40

8 Claims. 101. 269-295) I V g It has been found that hitherto. unknown derivatives of dihydro-pyridone can be obtained if strong acids, in presence or absence of a solvent, are caused to act on nitriles or amides of derivatives of a-cyano-w-acetyl-glutaric acid mono ester prepared by reacting i aldehydes simultaneously with acetoacetic ester and amide or nitrile derivatives of cyanacetic acid in presence of a secondary amine. As strong acids there may beusedany acid which in dilute aqueoussolution dissociates "practically completely, 1 especially strong mineral acids, such ashalogen acids, sulfuric acid, perchloric acid,a'nd others. But'also a strong organic acid, such asa sulfonic acid, for instance, methyl sulfonic gacid, phenyl sulfonic acid or a homologue can be employed; Ring closure is effected thereby with isomerisation when a nitrile is used or with elimination of one molecule of water, when employing an amide forming a derivative of dihydropyridone which carries a methyl-group in position 2,acarbalkoxy-group in position 3, a radical R in postion 4 corresponding to the radicalof the aldehyde used; in posi tion'5 a cyano-group, and imposition 6 the'-enolised oxo group of the pyridone.

A solvent is of advantage'if the directintimate contact between thestartingmaterial andthe acid cannot be brought about readily, for instance, if the acid is employed in the gaseous state, such as, for example, in the case of hydrogen chloride. Assolvents theremay be used all the known materials liquid at ordinary or slightly raised temperature which dissolve the starting material and the acid sufiiciently to ensure contact. These include alcohols, acids, suchas formic acid, acetic acid and homologues, halo1- genated hydrocarbons, such as chloroform, car- 1 bon tetrachloride and others, or suitablemixtures of the solvents amongst themselves, as Well as water. a

R can represent any organic, aliphatic, aromatic, aromaticaliphatic or cycloaliphatic radical, provided, of I course, that it does not itself undergo any changes under the reaction conditions, thus, for instance, R can represent an ali phatic radical such aszmethyl, ethyl, propyLis opropyl, butyl, homologues thereof andiisomers, allyl or, crotyl with, homologues and, isomers, as well. as an aromatic radical, such as, for instance, phenyl, b enzyl; styryl and their homologues: furthermore, zx- 2tnd p-naphthy'l and other radicals of condensedring syst'emdjas well as their'homo-- logue's', ora cycloaliphatic radical, such 'as cyclo and their homologues "and analogues. B may also bea hydrocarbon radi cal containing substituents, suchas halogen, a free or protected hydroXy-group, a nitro-group,,- oarboxyl-group, and-other radicals. Those com-r V pounds'are of special interest in xwhichthe radi cal; R represents a hydroxyemethyl-group -CH2-+O-'R" etherified by a radical R", where: in R a'ls'ostandsfor an aliphatic, aromatic or ialicyclic; radical, such as, for instance, an-ali-i phatic radical, such as methy1,-ethyl; propyl, isopropyl, butyl and its isomers and homologues, allyl, crotyl and isomers andhomologues, or an aromatic radicaLsuch as phenyl, ocand li -naphthyland other radicals oi'condensed ring systems, while radicals composed of an aliphatic and aromatic radical, such as beiizyl; phenylethyl, naphthylmethyl and homologues of these compounds can also be employed.

The reactibnis illustrated by the following structural'Formula A or B, as the case may be:

ammonia. A further tautomerisrn of the double,

bond of the nitrogen atom, according to Formula C, can also occur. x

R: I ('33: 1 Nc o \eg ogclm Hofr'i V I k t-Pom provided ,conditions'tending to 'saponify the'esterified carboxyl-group 'are not used. The said 7 compounds: are to be employed as intermediates for the manufacture of medicinal preparations;

ENT,

crystals. 7 tained in accordance with Example 1. The yield Example 1 '7 100 parts by volume of ethyl-alcohol are saturated with hydrochloric' acid gas at 20-30 CL Then 50 parts by weight of a-cyano-B-phenyl-w. acetyl-glutaric' acid moncethylester mononitrile are added and the whole shaken. ;The mixture becomes slightly warmand the -nitrile go'es 'intosolution within minutes. Theiproduct is left to stand for a further 10, minutes at 30 3 and then poured into 500 parts byweight of .gwa-l ter.

The melting point lies at 141 C.

Example 2: 3x r 2,334,490, i tained if 50 parts by weight of a-cyano-p-phenoxymethyl-'y-acetyl-glutaricacidmonoethylester monoamide are brought into a mixture of 200 2rmethyl-3-carbethoxy d phenyl-cyano-' I dihydropyridone-6 quickly separates in crystalline form. It is sucked off and recrystallised} from benzene. The yield is nearly'quantitative.p

parts by weightof glacial acetic acid and 50 parts by weight of methanesulfonic acid and poured into Aft/HUGS its volumeof water after standing'forhalf-an-hour v "wherein R" is selected from the group con- 50 parts by weight of u-cyano-B phenyli ace-* I tyl-glutaric acid monoethylester monoamide are suspended in 250 parts by volume of glacial acetic acidfi 30 parts by weight of concentrated sul-k phuric acid are added to 'themixture whereupon the amide goes into solution with'slight evolution of heat. Theclear solution is'left to stand for-=10 minutes and-then poured into double the volumelof water.'- The reaction product separates in the'form of asyrup which soon. solidifies. to -It isidentical with the product" 013- is nearly, quantitative. 4

1 V e Eramplej a" s If. instead of aecyanoefl-phenyl-v-acetyl-glu- I taric acid monoethylester ,monoamide; as employed'in Example 2, 50- parts by weight of; a-cyano-c-p-nitrophenyl 'y acetyl-glutaric acid ester amide are used. and: if. the working-up proceeds inv a manner analogous to the directions given in- Example 2,'2-methyl-3-carbethoxy-4 -p -nitrophenyl 5 cyanodihydropyridone-6 is obtained in practically quantitative yield. -It crystallises from alcohol in slightly yel melting point 129 C.

, 1 Example 4 V 10 parts by weight 'of a-cyano-B-isopropylacetyl-glutaric acid monoethylester mononitrile are suspended in 100 parts by volume of alcohol and 10 parts by weight of fuming aqueous hydrobromic acid added. The mixture is' heated to 50-60" C. with stirring until all has gone into lowish prisms of 1 solution. It is then cooled and poured into much water, or the greater part ofthe alcohol is distilled off and the residue diluted with water. 2- methyl-3-carbethoXy-4-isopropyl -5'- cyano-dihw GrOpyridone-S'lseparates as an; oil-which, Hon

inoculation or on standing for some time, crystallises spontaneously. Itlcan be recrystallised from a littlemethanoh I JEasample 50' parts by weight of oz-CYEtIlO-B-PhGHOXY- '7 methyl- -acetyl-glutaric' acid monoethylester mononitrile are dissolved in Qparts by weight of 5 per cent alcoholic hydrochloric acid and the mixtureheated to 60? C; fOr IO 'minutes. It is poured into water whereupon Z-methyl-S-carbethoxy--phenoxymethyl-5cyano dihydropyridone-6 separates as a syrup, which, on standin solidifies to, av crystalline mass. Frorn alcohcl or glacial --acetic acid; it i crystallises in 1 small rosettes of prismssmelting at 152C.

' Example- 6 V f {same compound as in Example ,5 is ch wherein X is selected fromthe group consisting ative of the formula sisting of alkyl, aryl, aralkyl, and cycloalkyl radicals, and R represents lower alkyl.

Y '2; 2-methyl-3-carbethoxy-4-phenoxymethyle 5-cyano-dihydro-pyridone (6),

pound of, the formula c v R I V v I r Nc-Hc \c r-coon' bro -ear,

wherein R is selected from the'g roup consist; ing of alkyl, alkoxyalkyl, cycloalkoxyalkyl,. aryl oxyalkyl, aralkyloxyalkyl; faryl aralkyl, and c cycloalkyl radicals, and 1. R represents lower alkyl, comprising treating a icals', and R "represents loweralkyl, compris- 'ing treating a glutaric acid derivative of the formula ,CHzO-R" of '-CONH2 and CN, with a 'strong'acict j 5; Process for the manufacture of Z -methyl i i lk XY- phenoxymethyl 5 cyanopyridone-(6); comprising treating -cyano-fl-phernoxymethyl-v-acetyl glutaric acid monoalkyl ester mononitrile with alstrongacid.

6. Process for the manufacture of, Z-methyI- 3-carbethoxy-4 phenoxymethyl 5 'cyanopyridone-(6)., comprising treating a-cyano-pfphe- 3. Process for the. manufacture of a 7' glutaric acid deriv noxymethyl-'y-acetyl-glutaric acid monoethylester mononitrile with a strong acid.

7. Process for the manufacture of 2-methy1- 3-carba1kqxy 4 phenoxymethyr 5 cyamopyridone-(6), comprising treating a-cyano-p-phenoxymethyl--y acety1-g1utaric acid mono-alkylester monoamide with a strong acid.

8. Process for the manufacture of 2-methy1- 3-carbethqxy-4 phenoxymethyl 5 -cyamopyr;idone-(6), comprising treating. a-cyano-p-phenoxymethyl-v-acetyl-glntaric acid. monoethyl- 5 ester monoamide with a strong acid.

MAX I-IOFFER. 

